The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes

Abstract

The 70 kDa heat-shock protein (HSP70) family is important for a dynamic range of cellular processes that include protection against cell stress, modulation of cell signalling, gene expression, protein synthesis, protein folding and inflammation. Within this family, the inducible 72 kDa and the cognate 73 kDa forms are found at the highest level. HSP70 has dual functions depending on location. For example, intracellular HSP70 (iHSP70) is anti-inflammatory whereas extracellular HSP70 (eHSP70) has a pro-inflammatory function, resulting in local and systemic inflammation. We have recently identified a divergence in the levels of eHSP70 and iHSP70 in subjects with diabetes compared with healthy subjects and also reported that eHSP70 was correlated with insulin resistance and pancreatic β-cell dysfunction/death. In the present review, we describe possible mechanisms by which HSP70 participates in cell function/dysfunction, including the activation of NADPH oxidase isoforms leading to oxidative stress, focusing on the possible role of HSPs and signalling in pancreatic islet α- and β-cell physiological function in health and Type 2 diabetes mellitus.

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

“…In a recent study, our group observed that the ratio between plasma eHSP70 and cellular iHSP70 in lymphocytes from rats submitted to different loads of acute exercise (an acute stressful situation) can indicate the inflammatory status [34]. Indeed, extracellular to intracellular HSP70 ratio index (H-index) measured in peripheral blood mononuclear cells (PBMC) in relation to serum values has been recently assumed as novel and overall index of immunoinflammatory status of an individual [34,39,105,112]. The rationale for this is that the higher eHSP70 amounts, the more inflammatory signals are coming into play because eHSP70 is proinflammatory in nature.…”

“…Therefore, HSPs may be envisaged as potential therapeutic tools to prevent neurodegeneration by avoiding protein aggregation processes, thus reducing the toxicity of such oligomers [170]. However, more studies are required to identify the specific signaling pathways and routes of administration of HSP70 to avoid possible harmful effects because, if HSP70 is not accurately introduced inside brain cells, it could remain within the extracellular space, where eHSP70s is a pro-inflammatory by virtue of what the binding to TLR2 and TLR4, at least in other cells, may exert [62,112]. Still in support of a major role of HS response for normal brain function, numerous studies have shown that the plant polyphenol resveratrol (3,5,4′-trihydroxystilbene) may extend the lifespan of several species, preventing age-related diseases beside possessing anti-inflammatory action.…”

“…Indeed, elevated levels of eHSP70 are positively associated with insulin resistance in elderly volunteers and induce TLR-dependent β cell failure [62]. Because of this, detection of plasma eHSP70 when not linked to any acute stress (e.g., exercise, α-adrenergic stimulation) is reputed as a marker of inflammationassociated chronic stress [34,47,112].…”

“…Interestingly, lower plasma glutamine availability and reduced basal and induced levels of HSP70 are also characteristics of obese, insulin-resistant, and T2DM people. Similarly to the elderly, these people also present reduced muscle mass (sarcopenic obesity) [327] and lowgrade inflammation [7,112].…”

“…Extracellular HSP70 and the role of HSP70 balance between intra-and extracellular space in inflammation After both acute and chronic stressful situations, HSPs can also be found in the extracellular milieu (eHSP70). This happens following a finely concerted secretion, mainly from lymphocytes and tissues from the hepatosplanchnic territories [34,112]. In general, eHSP70 acts as an alert signal to physiological systems for the presence of homeostatically threatening situations [105].…”